The function of signal transduction pathway by vascular endothelial growth factor (VEGF) is promoting angiogenesis. Angiogenesis means the formation of new capillaries from original blood vessels. Abnormalities of angiogenesis regulation relate to pathogenic mechanisms of many diseases, and are also a feature of many types of cancer. The main roles participating in the signal transduction pathway are proteins belonging to a vascular endothelial growth factor family and receptors thereof. Activation of this signal transduction pathway activates complex networks downstream, and promotes the growth, migration and survival of vascular endothelial cells. This signaling transduction pathway is regarded as being closely connected to tumor angiogenesis, so the inhibition of signal transduction pathway is important for the regulation of tumor angiogenesis.
The vascular endothelial growth factor family comprises a group of homologous dimeric glycoproteins having highly conserved sequences. The members in the vascular endothelial growth factor family are activated by linking two 24 kDa single-stranded molecules through a disulfide bond. The known members in the vascular endothelial growth factor family include VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placenta growth factor (PlGF), and wherein VEGF-A is first found and studied most thoroughly, which plays a critical role in angiogenesis.
When the vascular endothelial growth factor binds to vascular endothelial growth factor receptors (VEGF receptor, VEGFR), the vascular endothelial growth factor receptors form a dimer and phosphorylate each other. There are seven Ig-like domains located in the extracellular region of the vascular endothelial growth factor receptor. Generally, domains 1 to 3 are responsible for binding with the ligands, and domains 4 to 7 are responsible for dimerization, phosphorylation and downstream signal transduction.
The vascular endothelial growth factor receptor belongs to the tyrosine kinase (TK) family and is a key member in the signal transduction pathway. It transducts the extracellular signals of inducing cell growth, proliferation and anti-apoptosis into the cell. There are three types of the vascular endothelial growth factor receptor: VEGFR-1 (also known as flt-1), VEGFR-2 (also known as KDR/flk-1) and VEGFR-3 (also known as flt-4). VEGF-A binds to VEGFR-1 and VEGFR-2, and these two receptors are both expressed in the vascular endothelial cells, and the signals of the vascular endothelial cell are mainly transducted through VEGFR-2. Although the binding affinity between VEGFR-1 and the ligands is 10-folds stronger than that between VEGFR-2 and the ligands, the kinase activity of VEGFR-1 is weaker. In another aspect, VEGFR-3 is mainly expressed in lymphatic endothelial cells.
In addition to being by original peripheral vascular endothelial cell proliferation, it is also known that the tumor angiogenesis is formed by attracting vascular endothelial progenitor cells to move to the tumor or peripheral regions thereof under the regulation of VEGFR-2, and then the vascular endothelial progenitor cells are differentiated into the vascular endothelial cells. Because the angiogenesis relating to vascular endothelial growth factor receptor occurs only in wound repair and menstrual cycles of women in a normal physiological condition, the influence of blocking the signal transduction pathway by vascular endothelial growth factor receptor is limited to the normal physiological function. As a result, inhibiting signal transduction pathway by vascular endothelial growth factor receptor becomes an important regulatory point of inhibition of tumor angiogenesis and leading to tumor cell death consequently. It had been reported that vascular endothelial growth factors are over-expressed in a variety of solid tumors, such as colorectal cancer, breast cancer, prostate cancer, and lung cancer.
Thus, there is need for developing a novel approach to block signal transduction pathway by vascular endothelial growth factor receptor.